Molecular Structure and Function of Crystallins

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gamma-crystallins are associated with cataract in both human and animal models. gS-crystallin is the major bg-crystallin in the adult human lens and has also been found to be induced in retinal pigment epithelium in models of macular degeneration. The gene for gS has been ablated in mouse, leading to disruption of normal fiber cell maturation. Yeast 2-hybrid experiments to determine interaction partners for gS are in progress. NMR structure analysis of mouse gS-crystallin has shown important roles for flexible linker and N-terminal regions in providing entropic contributions to protein solubility. We have also shown that the mutant protein forms amyloid-like plaques in the Opj lens. The structure of mutant gS associated with the mouse Opj cataract is now being determined and is shedding light on the processes of protein unfolding. This has implications for other protein folding diseases such as amyloid diseases. The structure and stability of g- and beta-crystallins are dependent on a pattern of highly conserved amino acid residues. This sequence signature is also present in non-lens relatives of the crystallins, such as absent in melanoma 1 (AIM1)a protein implication in control of malignancy in melanoma. However proteins like AIM1 which have a lower requirement for stability than crystallins may compromise structural stability for additional functional roles. In collaborative studies we have investigated the structure of the most divergent domain of human AIM1. X-ray analysis shows that the basic structure is conserved, while loss of key residues has loosened parts of the structure.